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Myeloablative conditioning using timed-sequential busulfan plus fludarabine in older patients with acute myeloid leukemia: long term results of a prospective phase II clinical trial
Mehta, R. S., Bassett, R., Olson, A., Chen, J., Ahmed, S., Alousi, A. M., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., et al
Haematologica. 2019
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[Autologous stem cell transplantation with a myeloablative regimen for treatment of severe systemic sclerosis]
Henes, J. C.
Zeitschrift fur Rheumatologie. 2018
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Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study
Dvorak, C. C., Satwani, P., Stieglitz, E., Cairo, M. S., Dang, H., Pei, Q., Gao, Y., Wall, D., Mazor, T., Olshen, A. B., et al
Pediatric blood & cancer. 2018
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Abstract
BACKGROUND Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less-toxic myeloablative conditioning regimen containing busulfan-fludarabine (Bu-Flu) would be associated with equivalent outcomes. PROCEDURE Twenty-seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre- and post-HCT (starting Day +30) mutant allele burden was measured in all and pre-HCT therapy was administered according to physician discretion. RESULTS Fifteen patients were randomized (six to Bu-Cy-Mel and nine to Bu-Flu) after meeting diagnostic criteria for JMML. Pre-HCT low-dose chemotherapy did not appear to reduce pre-HCT disease burden. Two patients, however, received aggressive chemotherapy pre-HCT and achieved low disease-burden state; both are long-term survivors. All four patients with detectable mutant allele burden at Day +30 post-HCT eventually progressed compared to two of nine patients with unmeasurable allele burden (P = 0.04). The 18-month event-free survival of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27-97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04). ASCT1221 was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. CONCLUSIONS The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management.
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Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma
Sullivan, K. M., Goldmuntz, E. A., Keyes-Elstein, L., McSweeney, P. A., Pinckney, A., Welch, B., Mayes, M. D., Nash, R. A., Crofford, L. J., Eggleston, B., et al
New England Journal of Medicine. 2018;378(1):35-47
Abstract
BACKGROUND Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed >=9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).
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High vs low dose Cyclosporine-A, after allogeneic marrow transplantation in leukemia: Long term follow up of a randomized study
Bacigalupo, A., Van Lint, M. T., Sica, S., Laurenti, L., Rosales, M. B., Dominietto, A., di Grazia, C., Angelucci, E.
American Journal of Hematology. 2018
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Stem Cell Transplantation Improves Scleroderma Outcomes
Slomski, A.
Jama. 2018;319(8):761
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A randomized phase II study of standard-dose versus high-dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B-cell non-hodgkin lymphomas: long term results
Srour, S. A., Li, S., Popat, U. R., Qazilbash, M. H., Lozano-Cerrada, S., Maadani, F., Alousi, A., Kebriaei, P., Anderlini, P., Nieto, Y., et al
British Journal of Haematology. 2017;178(4):561-570
Abstract
High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single-arm prospective study of relapsed aggressive B-cell non-Hodgkin lymphoma (R-NHL). We performed a randomized phase 2 study comparing HD-R versus standard-dose rituximab (SD-R) in R-NHL. Ninety-three patients were randomized to HD-R (1000 mg/m2 ) (n = 42) or SD-R (375 mg/m2 ) (n = 51) administered on post-transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow-up of 7.92 years, the 5-year disease-free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (36% vs. 43%; P = 0.205) and OS (43% vs. 52%; P = 0.392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1.79, 95% confidence interval [CI]: 1.08-2.95) and number of prior treatments received (>2 vs. <=2 lines of treatment) (HR 1.89, 95% CI: 1.13-3.18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received <=2 lines of treatment prior to SCT had better 5-year OS (57% vs. 35%; P = 0.02 and 54% vs. 30%, P = 0.001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B-cell NHL, HD-R provided no DFS or OS advantage over SD-R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri-transplant setting remains controversial.
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High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group
Kasenda, B., Ihorst, G., Schroers, R., Korfel, A., Schmidt-Wolf, I., Egerer, G., von Baumgarten, L., Roth, A., Bloehdorn, J., Mohle, R., et al
Leukemia. 2017;31(12):2623-2629
Abstract
To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL), we conducted a single-arm multicentre study for immunocompetent patients (<66 years) with PCNSL failing high-dose methotrexate)-based chemotherapy. Induction consisted of two courses of rituximab (375mg/m2), high-dose cytarabine (2 x 3g/m2) and thiotepa (40mg/m2) with collection of stem cells in between. Conditioning for HCT-ASCT consisted of rituximab 375mg/m2, carmustine 400mg/m2 and thiotepa (4 x 5mg/kg). Patients commenced HCT-ASCT irrespective of response after induction. Patients not achieving complete remission (CR) after HCT-ASCT received whole-brain radiotherapy. Primary end point was CR after HCT-ASCT. We enrolled 39 patients; median age and Karnofsky performance score are 57 years and 90%, respectively. About 28 patients had relapsed and 8 refractory disease. About 22 patients responded to induction and 32 patients commenced HCT-ASCT. About 22 patients (56.4%) achieved CR after HCT-ASCT. Respective 2-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% (median PFS 12.4 months) and 56.4%; median OS not reached. We recorded four treatment-related deaths. Thiotepa-based HCT-ASCT is an effective treatment option in eligible patients with r/r PCNSL. Comparative studies are needed to further scrutinise the role of HCT-ASCT in the salvage setting.
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Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma
Attal, M., Lauwers-Cances, V., Hulin, C., Leleu, X., Caillot, D., Escoffre, M., Arnulf, B., Macro, M., Belhadj, K., Garderet, L., et al
New England Journal of Medicine. 2017;376(14):1311-1320
Abstract
BACKGROUND High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation. METHODS We randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival. RESULTS Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy. CONCLUSIONS Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060).
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A Randomized Study Comparing Stem Cell Transplantation Versus Conventional Therapy for Low- and Intermediate-Risk Myelodysplastic Syndromes Patients
Yu, Z. P., Ding, J. H., Sun, A. N., Ge, Z., Chen, B. A., Wu, D. P.
Stem Cells & Development. 2017;26(15):1132-1139
Abstract
The treatment of myelodysplastic syndromes (MDS) involves improving patient survival and quality of life (QoL) and decreasing the likelihood of progression to AML. Although the treatment outcomes of MDS remain unsatisfactory, few comparative studies have been performed while comparing the outcomes of low-risk and intermediate-risk patients treated with supportive care and chemotherapeutics to those of patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we designed a clinical control study to compare the outcomes of supportive care and chemotherapeutics versus allo-HSCT treatment in MDS patients. A total of 182 patients with MDS were enrolled in the study, including 91 in the no-HSCT (control) group and 91 in the allo-HSCT group. The complete remission (CR) rate in the allo-HSCT group was significantly higher than that in the control group (53.8% vs. 33.0%; P<0.05). The QoL of patients in the HSCT group was much higher than that in the control group (53.8% vs. 37.4%; P<0.05). The overall survival (OS) rates were 79.0% and 56.0% (P<0.05) in the HSCT group and the control group, respectively. In conclusion, a high-dose fludarabine (Flu), busulfan (Bu), cyclophosphamide (CTX)-based conditioning regimen was well tolerated and significantly speeded hematopoietic recovery. In addition, this regimen increased procedure-related toxicity and improved QoL and OS.